Because of the ease of access, dynamics of application, large surface area, vast exposure to the circulatory and lymphatic networks, and non-invasive nature of the treatment, the delivery of pharmaceutically-active agents through the skin has long been a promising concept. This is true whether the bioavailability desired is systemic or dermal, regional or local.
The advantages of this form of delivery include, but are not limited to: avoidance of the risks associated with parenteral treatment; elimination of the inconveniences of parenteral treatment; avoidance of the variable rates of absorption and metabolism inherent in oral treatment; increasing the continuity of drug administration by permitting delivery of agents with short biological half-lives; and elimination of gastrointestinal irritation resulting from exposing the gastrointestinal tract to pharmaceutical actives, preservatives, tableting agents, and the like. Most importantly, topical delivery possesses the potential for effectively treating conditions which are local in nature (or which exhibit local manifestations), systemically as well as locally with the same treatment regimen. Thus, effective compositions to deliver pharmaceutical agents are highly sought after.
However, because it must serve as a barrier to the ingress of pathogens and toxic materials, and the egress of physiologic fluids, the skin is highly impermeable. It must be impermeable to preserve its own integrity while at the same time maintaining the delicate dynamic electrolyte balance of the body. The skin must serve a containment function; it must also function as a microbial, chemical, radiation and thermal barrier.
A good deal of this impermeability of the skin results from the nature of one very thin layer created by normal developmental and physiological changes in the skin. After cells are formed in the basal layer, they begin to migrate toward the skin surface, until they are eventually sloughed off. As they undergo this migration, they become progressively more dehydrated and keratinized. When they reach the surface, just prior to being discarded, they form a thin layer of dense, metabolically inactive cells approximately ten microns (10-15 cells) thick. This layer is called the stratum corneum or the "cornified layer". As a result of the high degree of keratinization of the cells which comprise the stratum corneum, a formidable barrier is created. Therefore, penetration via the nonpolar route, i.e., across the membrane of these cells, remains most difficult.
Other possible penetration routes are available. First, any mechanism which allows the egress of materials, e.g. the sebaceous apparatus, can be manipulated to allow the ingress of materials. Second, the stratum corneum, though keratinized to a great degree, is composed of about 15% lipid-based intercellular material. While it has been noted that this may offer a less formidable route despite the close packing of the cells, the integrity of the skin, and particularly the stratum corneum, has detracted from the overall promise of percutaneous delivery.
Accordingly, in an effort to take advantage of this route of administration and overcome the obstacles the skin naturally provides, the art has turned to the use of specifically selected vehicles and carriers into which the pharmaceutical active is incorporated so that the vehicle or carrier aids in, or at a minimum does not adversely affect, the penetration of the selected active. The art recognizes that to a vast degree the rate of percutaneous delivery of a pharmaceutical active can be significantly decreased by the selection of an improper vehicle.
One of the newest compounds thought to increase the permeability of the skin, when used as or within a vehicle, is the compound 1-dodecyl-azacycloheptan-2-one (Azone). Azone is a colorless and virtually odorless compound of the formula ##STR1## It is reported to have a low order of toxicity with a lethal dose for 50% survival (LD.sub.50) in the range of about 8 g/kg in rats. The compound is stable over a period of approximately four years.
Azone has been demonstrated to enhance the cutaneous penetration of clindamycin phosphate, erythromycin base, fusidate sodium, fluorouracil, desonide, amcinonide and triamcinolone acetonide. Other n-substituted-azacycloheptan-2-ones of the formula ##STR2## wherein R is a straight or branched chain alkyl group having 1-18 carbon atoms or an aryl group, e.g., phenyl, R.sup.1 is H or a lower alkyl group having 1-4 carbon atoms, and n is 0 or a positive integer from 1-10, are also known to aid in the penetration of topically administered physiologically active agents. These compounds have also been described as being useful in aiding in the penetration of certain anti-bacterial agents, antibiotics (particularly lincomycin, clindamycin, tetracycline and erythromycins), steroids, anti-fungal agents, iododeoxyuridine, sunscreens and allergens.
It has now been discovered that the penetration-enhancing efficacy of 1-dodecyl-azacycloheptan-2-one can be significantly improved when it is used in a select, binary combination with certain other penetration-enhancing agents or polar solvents. Specifically, it has been discovered that a binary penetration system comprising Azone in combination with a diol, certain other n-substituted-alkyl-azacycloalkyl-2-ones, or mixtures thereof, consistently and dramatically demonstrates improved topical delivery of certain pharmaceutically-active agents, such as steroids, when the second component is used at specific levels and when the components of the binary combinations are present at specific ratios.
U.S. Pat. No. 3,989,816, Rhaadhyaksha, issued Nov. 2, 1976, discloses a method for enhancing the penetration of pharmaceutical actives through the skin or membranes comprising dissolving an effective amount of the selected agent in a carrier containing a 1-substituted-azacycloheptan-2-one, and, in turn, contacting the skin or membrane with the resulting composition. The actives specifically disclosed include antibacterial agents, antibiotics, steroids, antifungals, allergens, and sunscreens. The specification describes a host of "typical inert carriers" appropriate for formulating a vehicle which contains this compound. These inert carriers include water, acetone, isopropyl alcohol, Freons, ethyl alcohol, polyvinylpyrrolidone, and propylene glycol, as well as polysorbates and tweens.
Stoughton, "Enhanced Percutaneous Penetration with 1-dodecylazacycloheptan-2-one", Arch. Derm., 118, pp. 474-477 (1982), discusses the ability of Azone to aid in the penetration of clindomycin phosphate, erythromycin base, fusidate sodium, fluoroucil, desonide, amcinonide, and triamcinolone acetonide. He states that vehicles such as dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide, 1-methyl-2-pyrrolidone and propylene glycol and "grossly influence" the penetration of an agent through the stratum corneum into the corium.
U.S. Pat. No. 4,132,781, Stoughton, issued Jan. 2, 1979, discloses topical antibacterial compositions containing an antibiotic (of the erythromycin family) in combination with 2-pyrrolidone or an n-lower alkyl-2-pyrrolidone which are useful in the treatment of acne.
U.S. Pat. No. 4,017,641, DiGiulio, issued Apr. 12, 1977, describes skin conditioning compositions containing 2-pyrrolidone. A composition is disclosed which further contains 2.5% propylene glycol.
It is known that certain binary skin penetration systems can increase the disorder of lipids in the skin. By so increasing the disorder of the lipid portion of the cell-envelope in the stratum corneum, the lipid packing of the cells can be disrupted. This disruption allows certain pharmaceutically active agents to pass through the stratum corneum. This discovery has been confirmed by differential scanning calorimetry, indicating that certain binary skin penetration enhancement systems eliminate the Tm-2 peak associated with melting of cell-envelope lipids. This U.S. patent application Ser. No. 296,706, Cooper, et al., filed Aug. 27, 1981, describes compositions for topical application. These compositions are described as suitable for effective delivery of lipophilic, pharmacologically-active compounds using primary alcohols or various carboxylate compounds in combination with selected diols. See European Patent Application No. 43,738, published Jan. 13, 1982.
U.S. Pat. No. 4,343,798, Fawzi, issued Aug. 10, 1982, describes topical antimicrobial/anti-inflammatory compositions containing C.sub.5 -C.sub.12 fatty acids in combination with corticosteroids.
U.S. Pat. No. 3,934,013, Poulsen, issued Jan. 20, 1976, describes topical pharmaceutical compositions containing at least two corticosteroids, propylene glycol, a fatty alcohol and water. The patenee describes the "fatty alcohol ingredient" as any fatty alcohol having from 16-24 carbon atoms and, preferably, as a saturated, monohydric primary alcohol such as cetyl alcohol, stearyl alcohol or behenyl alcohol.
U.S. Pat. No. 4,289,764, Yarrow, et al., issued Sept. 15, 1981, describes topical pharmaceutical compositions with increased shelf stability. These compositions comprise a steroid, 15-50% by weight propylene glycol and are buffered to a pH of 2.7-3.3. The specification describes the desirability of thickening the propylene glycol (due to its low viscosity) with a compound selected from long-chain paraffins, fatty alcohols, and waxes, including cetyl stearyl alcohol, white soft paraffin and liquid paraffin.
U.S. Pat. No. 4,070,462, Ecker, issued Feb. 24, 1978, discloses a topical vehicle which includes (i) 5-15% 1,2-propanediol, 2,3-butanediol or 2methyl-2,4,-propanediol; (ii) 1-3% propylene glycol monostearate; and (iii) petrolatums and waxes to 100%.
U.S. patent application Ser. No. 001,974, Wickett, et al., filed Jan. 8, 1979, now abandoned describes compositions useful in the treatment of acne. These compositions contain benzoyl peroxide, C.sub.6 -C.sub.14 primary alcohols, and a diol selected from 1,2-propanediol, 1,2-butanediol, 1,3-butanediol, and 2,3-butanediol. A foreign equivalent of this application was made available to the public July 23, 1980. See European Patent Application No. 13,459.
U.S. patent application Ser. No. 383,391, Cooper, filed June 1, 1982, now abandoned discloses and claims a binary penetration system utilizing a diol and a cell-envelope disordering compound to aid in the penetration of 9-hydroxyethoxymethyl (and related) derivatives of 6- and 2,6-substituted purines. These compounds are reported to be effective in the treatment of viral infections, especially herpes.
1,2-propanediol ("propylene glycol") and the C.sub.10 -C.sub.14 alcohols have been used, separately, in cosmetic and pharmaceutical formulations. In particular, propylene glycol has been described in several articles in the literature as enhancing the penetration of certain pharmacologically active agents, such as the corticosteroids. See Rosuold, J., et al., "Effect of Formulation On In Vitro Release and In Vivo Absorption of Corticosteroids from Ointments", Medd. Novsk Favm Selsk, 44, 21-45 (1982); see also, Anjo, D. M., et al., "Methods for Predicting Percutaneous Penetration in Man", Percutaneous Absorption of Steroids. pp 31-51, Academic Press, New York, N.Y. (1980), both incorporated herein by reference.
U.S. Pat. No. 3,535,422, Cox, et al., Oct. 20, 1970, relates to stable benzoyl peroxide compositions containing organic emollients. The compositions include emollients selected from the C.sub.4 -C.sub.20 aliphatic alcohols, C.sub.2 -C.sub.3 glycols, C.sub.12 -C.sub.20 fatty acids and their esters, and mixtures thereof.
U.S. Pat. No. 4,070,462, Ecker, issued Jan. 24, 1978, describes topical steroid compositions containing 6% propylene glycol and 1% propylene glycol monostearate.
Canadian Pat. No. 1,072,009, Sipos, issued Feb. 19, 1980, describes topical antimicrobial compositions containing C.sub.5 -C.sub.10 straight chain alcohols or C.sub.17 branched chain alcohols in which the longest chain is C.sub.5 -C.sub.10.
CA 92:153,181j; describes an indomethacin ointment containing 10% propylene glycol and 1.1% diisopropanolamine.
U.S. Pat. No. 2,990,331, Neumann, et al., issued June 27, 1961, describes tetracycline compositions containing carboxylic acid alkylolamides.
H. Barnes, et al., Br. J. Derm. 93, 459 (1975), describe testing of fluocinonide and fluocinolone acetonide in a vehicle described as fatty alcohol propylene glycol (FAPG).
P. J. W. Ayres, et al., Br. J. Derm., 99, 307 (1978), report comparative skin penetration of cortisol from commercially available cortisol ointments.
Schaaf and Gross, Dermatologica, 106, 357 (1953), note that unsaturated fatty acids and C.sub.6 -C.sub.14 saturated fatty acids are particularly active in provoking epidermal thickening.
J. Zatz, et al., J. Pharm. Sci., 67, 789 (1978), describe the effect of formulation factors on penetration of hydrocortisone through mouse skin.
S. K. Chandrasekaran, et al., J. Pharm. Sci., 67, 1370 (1978), discuss the pharmacokinetics of drug permeation through human skin.
B. Idson, Cosmetics & Toiletries, 95, 59 (1980), states that the factors affecting drug penetration and, consequently, in most cases, effectiveness, are complex. He observes that the vehicle that provides ideal conditions for one drug may prove unsatisfactory for another. The author concludes that prediction is not simple and product suitability must be assessed by human trials. The same article indicates that Synalar Cream, a topical corticosteroid preparation, contains sorbitan monooleate and propylene glycol.
M. M. Rieger, Cosmetics & Toiletries, 94, 32-37 (1979) and 95, 26-38 (1980), provides a review of current literature in the area of skin penetration.
U.S. Pat. No. 4,299,826, Luedders, issued Nov. 10, 1981, describes a composition for the treatment of acne by using diisopropyl sebacate as a penetration enhancer for an erythromycin derivative in combination with an alcohol.
U.S. Pat. No. 2,990,331, Neumann, et al., issued June 27, 1961, describes the parenteral administration of tetracycline salts from a stable aqueous solution.
CA 79: 122,308, describes an electromagnetic study of n-alkyl ionic surfactants as aiding in human epidermis penetration.